Pyridyl alkylguanidine compounds, composition therewith, and methods of inhibiting H-2 histamine receptors

ABSTRACT

The compounds are pyridyl alkylguanidines, for example N-benzenesulphonyl-N&#39;-methyl-N&#34;-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine, which are inhibitors of histamine activity.

This application is a continuation-in-part of Ser. No. 384,992 filedAug. 2, 1973, now abandoned.

This invention relates to pharmacologically active compounds, inparticular to pharmacologically active guanidines, to processes ofpreparing these compounds and the pharmaceutical compositions andmethods of inhibiting H-2 histamine receptors with these compounds. Thecompounds of the invention can exist as the addition salts but, forconvenience, reference will be made throughout this specification to theparent compounds.

It has long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyramine is a typical example) is believed to involve a receptorwhich has been designated as H-1. A further group of substances hasrecently been described by Black et al. (Nature 1972, 236, 385) whichare distinguished by the fact that they act at histamine receptors otherthan the H-1 receptor and these other receptors have been designated asH-2 receptors. This latter group of substances, to certain of which thepresent invention relates, are thus of utility in inhibiting certainactions of histamine which are not inhibited by the above-mentioned"antihistamines". Black, et al., cited above, page 390, column 2, statethe following: "Mepyramine has been defined as an H₁ -receptorantagonist and burimamide has now been defined as an H₂ -receptorantagonist. Used alone, burimamide can antagonize those responses tohistamine, such as stimulation of acid gastric secretion, which cannotbe blocked by mepyramine; histamine apparently activates H₂ -receptorsto produce these effects." Thus, from the Black et al. paper, H-2histamine receptors are those histamine receptors which are notinhibited by mepyramine but are inhibited by burimamide. The substancesof this invention may also be of utility as inhibitors of certainactions of gastrin.

Throughout the present specification and claims, by the term "loweralkyl" we mean an alkyl group containing from 1 to 4 carbon atoms. Theguanidines with which the present invention is concerned may berepresented by the following general formula: ##EQU1##

FORMULA I

wherein R₁ is hydrogen or lower alkyl such as methyl; R₂ is a groupingof the structure shown in Formula II:

    het -- (CH.sub.2).sub.m Z(CH.sub.2).sub.n --

FORMULA II

wherein Het is a pyridyl ring which is optionally substituted by loweralkyl, trifluoromethyl, hydroxyl, halogen or amino; Z is sulphur,oxygen, NH or a methylene group; m is 0, 1 or 2 and n is 2 or 3 the sumof m and n being from 2 to 4; X is COR₃, CSR₃, SO₂ R₄, N=CHR₅ or, when Zis methylene, nitro; R₃ is lower alkyl, lower alkoxy or, when Z issulphur, oxygen or NH, amino; R₄ is lower alkyl, trifluoromethyl, aminoor substituted or unsubstituted aryl, such as phenyl optionallysubstituted by halogen, lower alkyl or amino; and R₅ is substituted orunsubstituted aryl, such as phenyl or pharmaceutically acceptable acidaddition salts therefor.

It will be understood that the structure illustrated in Formula I isonly one of several representations and that other tautomeric forms arealso covered by the present invention.

In a preferred group of compounds R₁ is methyl, R₂ is preferablyHet--CH₂ S (CH₂)₂ and is particularly preferably such that Het is apyridyl ring, which ring is optionally substituted by methyl, hydroxyl,halogen or amino. Useful compounds are also obtained when X isphenylsulphonyl, aminosulphonyl or aminocarbonyl.

The compounds of the present invention may be produced from an amine ofthe formula R₂ NH₂, wherein R₂ has the same significance as in Formula Iby reaction thereof with a compound of Formula III. ##EQU2##

FORMULA III

wherein R₁ and X have the same significance as in Formula I; Y issulphur or oxygen; and A is lower alkyl e.g., methyl.

Alternatively, reaction of the amine of formula R₂ NH₂ with a compoundof Formula IV:

    (a--y).sub.2 c = n -- x

formula iv

wherein A, Y and X have the same significance as in Formula III resultsin the production of an intermediate compound of the following FormulaV: ##EQU3##

FORMULA V

wherein A, Y, X and R₂ have the above significance. Reaction of thisintermediate with R₁ NH₂ wherein R₁ is hydrogen or lower alkyl yieldsthe required compound of Formula I. This reaction scheme is particularlysuitable for the production of those compounds wherein X is SO₂ R₄. Thecompound of Formula IV wherein Y is sulphur is preferred and may beproduced by the reaction of an aminosulphonyl compound of the formula R₃SO₂ NH₂ under alkaline conditions with carbon disulphide and an alkylhalide of formula R₁ Hal wherein R₁ is lower alkyl and Hal is a halogensuch as iodine.

Certain specific methods may also be used for the production of someparticular compounds of Formula I. For example to produce thosecompounds wherein X is aminosulphonyl a guanidine of Formula VI;##EQU4##

FORMULA VI

wherein R₁ and R₂ have the same significance as in Formula I may bereacted with a diaminosulphonyl compound of Formula VII.

    w = n.so.sub.2 nh.sub.2

formula vii wherein W is derived from a secondary amine of formula W=NHe.g., piperidine.

A further specific method which may be used to produce those compoundsof Formula I wherein X is aminocarbonyl involves mild acid hydrolysise.g., with dilute hydrochloric acid at from 20°C to 50°C of acyanoguanidine compound of Formula VIII. ##EQU5##

FORMULA VIII

wherein R₁ and R₂ have the same significance as in Formula I. Thecompounds of Formula I wherein X is aminothiocarbonyl may also beprepared from the cyanoguanidine of Formula VIII by reaction thereofwith hydrogen sulphide in a solvent such as pyridine and in the presenceof a strong base such as triethylamine.

As stated above, the compounds represented by Formula I have been foundto have pharmacological activity in the animal body as antagonists tocertain actions of histamine which are not blocked by "antihistamines"such as mepyramine. For example, they have been found to inhibitselectively the histamine-stimulated secretion of gastric acid from theperfused stomachs of rats anaesthetised with urethane at doses of from 1to 256 micromoles per kilogram intravenously.

Similarly, the action of these compounds may, in many cases, bedemonstrated by their antagonism to the effects of histamine on othertissues which, according to the above mentioned paper of Black, et al.,are mediated by H-2 receptors. Examples of such tissues are perfusedisolated guinea-pig heart, isolated guinea-pig right atrium and isolatedrat uterus. The compounds of the invention have also been found toinhibit the secretion of gastric acid stimulated by pentagastrin or byfood.

The level of activity found for the compounds of the present inventionis illustrated by the effective dose range in the anaesthetised rat, asmentioned above of from 1 to 256 micromoles per kilogram, givenintravenously. Many of the compounds of the present invention produce a50% inhibition in this test at a dose of from 3 to 15 micromoles perkilogram.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of inhibiting the H-2 histamine receptors whichcomprises administering to an animal a compound of Formula I or apharmaceutically acceptable acid addition salt thereof are also objectsof this invention.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 gm. If a liquid carrier is used,the preparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg. to about 250 mg., most preferably from about100 mg. to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto three times per day. The daily dosage regimen will preferably be fromabout 150 mg. to about 750 mg., most preferably from about 300 mg. toabout 600 mg.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the compositions will bemade up in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule, injectable solution oras a cream for topical administration.

The invention is illustrated but in no way limited by the followingexamples:

EXAMPLE 1 N-Benzenesulphonyl-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine

A solution of N-benzenesulphonyliminodithiocarbonic acid dimethyl ester(13.0 g) and 3-hydroxy-2-((2-aminoethyl) thiomethyl)pyridine (9.2 g) inethanol (100 ml) was stirred at room temperature for 4 hours. Excessethanolic methylamine was added and stirring was continued for 2 hoursat room temperature. Following concentration, the residue wasrecrystallised to giveN-benzenesulphonyl-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 2 N-[4-(2-Pyridyl)butyl]-N'-nitroguanidine

A solution of 2-(4-aminobutyl)pyridine (2.9 g) andS-methyl-N-nitroisothiourea (2.9 g) in methanol (50 ml) was heated at50°-65° for 4-5 hours. Concentration, followed by recrystallisation ofthe residue yielded N-[4-(2-pyridyl)butyl]-N'-nitroguanidine.

EXAMPLE 3N-Methyl-N'-[2-((3-chloro-2-pyridyl)methylthio)ethyl]-N"-trifluoromethanesulphonylguanidine

a. A mixture of trifluoromethylsulphonamide (4.2 g) andbis-S-methylthio-N-methylformimine, (7.6 g) was heated at 120° for 4hours. Cooling, followed by the addition of hexane affordedN,S-dimethyl-N'-trifluoromethanesulphonylisothiourea (5.0 g) m.p.88°-89°.

(Found: C, 20.3; H, 3.0; N, 11.9; S, 27.2. C₄ H₇ F₃ N₂ O₂ S₂ requires:C, 20.3; H, 3.0; N, 11.9; S, 27.2).

b. A solution of 3-chloro-2-((2-aminoethyl)thiomethyl) pyridine (4.1 g)and N, S-dimethyl-N'-trifluoromethanesulphonylisothiourea (4.9 g) inethanol (50 ml) was heated under reflux for 24 hours. Concentration,followed by chromatographic purification on a column of silica gelyieldedN-methyl-N'-[2-((3-chloro-2-pyridyl)methylthio)ethyl]-N"-trifluoromethanesulphonylguanidine.

EXAMPLE 4N-(4-Chlorobenzenesulphonyl)-N'-methyl-N"-[2-((3-bromo-2-pyridyl)methylthio)ethyl]guanidine

a. A mixture of 4-chlorobenzenesulphonamide (6.0 g) andbis-S-methylthio-N-methylformimine (8.5 g) was heated at 120°-125° for 4hours to give N-(4-chlorobenzenesulphonyl)-N',S-dimethylisothiourea (5.8g), m.p. 121°-123° (from ethanol-hexane).

Found: C, 38.5; H, 4.1; N, 9.9; Cl, 12.7; S, 22.8; C₉ H₁₁ Cl N₂ O₂ S₂requires: C, 38.8; H, 4.0; N, 10.1; Cl, 12.7; S, 23.0).

b. A solution of 3-bromo-2-((2-aminoethyl)thiomethyl) pyridine (5.0 g)and N-(4-chlorobenzenesulphonyl)-N',S-dimethylisothiourea (5.4 g) inacetonitrile was heated under reflux for 24 hours. Concentrationfollowed by recrystallisation affordedN-(4-chlorobenzenesulphonyl)-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine.

EXAMPLE 5N-(3,4-Dichlorobenzenesulphonyl)-N'-methyl-N"-[2-((6-methyl-2-pyridyl)methylthio)ethyl]guanidine.

a. A mixture of 3,4-dichlorobenzenesulphonamide (6.5 g) andbis-S-methylthio-N-methylformimine (8.0 g) was heated at 120° for 4hours to give N-(3,4-dichlorobenzenesulphonyl)-N',S-dimethylisothiourea(7.3 g) m.p. 158°-159° (from methanol).

(Found: C, 34.4; H, 3.1; N, 8.9; Cl, 22.9; S, 20.4. C₉ H₁₀ Cl₂ N₂ O₂ S₂requires: C, 34.5; H, 3.2; N, 8.9; Cl, 22.6; S, 20.2).

b. A solution of 6-methyl-2-((2-aminoethyl)thiomethyl) pyridine (3.7 g)and N-(3,4-dichlorobenzenesulphonyl)-N', S-dimethylisothiourea (6.2 g)in acetonitrile (250 ml) was heated under reflux for 48 hours.Concentration, followed by chromatographic purification on a column ofalumina affordedN-(3,4-dichlorobenzenesulphonyl)-N'-methyl-N"-[2-((6-methyl-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 6N-Benzenesulphonyl-N'-[2-((3-methyl-2-pyridyl)methylthio)-ethyl]guanidine

A solution of 3-methyl-2-((2-aminoethyl)thiomethyl)pyridine (6.3 g) andN-benzenesulphonyl-S-methylisothiourea (8.0 g) in acetonitrile (100 ml)was heated under reflux for 24 hours. Concentration, followed bychromatographic purification on a column of silica gel andrecrystallisation affordedN-benzenesulphonyl-N'-[2-((3-methyl-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 7N-Methanesulphonyl-N'-methyl-N"-[2-((2-pyridyl)methylthio)-ethyl]guanidine

A solution of N-methanesulphonyliminodithiocarbonic acid dimethyl ester(10.0 g) and 2-((2-aminoethyl)thiomethyl)-pyridine (8.5 g) in ethanol(100 ml) was stirred at room temperature for 3 hours. Excess ethanolicmethylamine was added and stirring continued for 3 hours at roomtemperature. Concentration and trituration with ice-water affordedN-methanesulphonyl-N'-methyl-N"-[2-((2-pyridyl)methylthio)-ethyl]guanidine.

EXAMPLE 8 N-Ethanesulphonyl-N'-methyl-N" -[2-((4-pyridyl)methylthio)ethyl]guanidine

To a solution of ethanesulphonamide (12.0 g) in dimethylformamide (75ml) at 4°, was added a solution of sodium hydroxide (4.45 g) in water (6ml) and carbon disulphide (3.6 ml). After stirring for 10 minutes at 5°sodium hydroxide (2.2 g) in water (3 ml) and carbon disulphide (1.5 ml)was added and after a further 10 minutes similar quantities of sodiumhydroxide and carbon disulphide were again added. After stirring for 10minutes at 5°, methyl iodide (42.6 g) was added without external coolingand stirring was continued for 2 hours and the reaction mixture added towater (750 ml). Extraction with ether and concentration yielded crudeN-ethanesulphonyl-iminodithiocarbonic acid dimethyl ester (6.4 g). Thiswas reacted directly with 4-((2-aminoethyl)thiomethyl)pyridine (5.0 g)and methylamine in ethanol by the method described in Example 7. Theproduct was chromatographed on a column of silica gel to yieldN-ethanesulphonyl-N'-methyl-N"-[2-((4-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 9N-Methyl-N'-[2-((3-amino-2-pyridyl)methylthio)ethyl]-N"-n-propanesulphonylguanidine

a. Reaction of n-propanesulphonamide with sodium hydroxide carbondisulphide and methyliodide by the method described in Example 8afforded N-n-propanesulphonyliminodithiocarbonic acid dimethyl ester,m.p. 73°-74° (from ethanol-hexane).

(Found: C, 31.7; H, 5.7; N, 6.2; S, 42.0. C₆ H₁₃ NO₂ S₃ requires: C,31.7; H, 5.8; N, 6.2; S, 42.3)

b. The reaction of N-n-propanesulphonyliminodithiocarbonic acid (4.7 g)dimethyl ester with 3-amino-2-((2-aminoethyl)thiomethyl)pyridine (3.7 g)and methylamine by the method described in Example 7 followed bychromatographic purification on a column of silica gel affordedN-methyl-N'-[2-((3-amino-2-pyridyl)methylthio)ethyl]-N"-n-propanesulphonylguanidine.

EXAMPLE 10N-Methyl-N'-[2-((5-trifluoromethyl-2-pyridyl)methylthio)-ethyl]-N"-p-toluenesulphonylguanidine

The reaction of N-p-toluenesulphonyliminodithiocarbonic acid dimethylester (10.0 g) with5-trifluoromethyl-2-((2-aminoethyl)thiomethyl)pyridine (8.6 g) andmethylamine by the method described in Example 6, affordedN-methyl-N'-[2-((5-trifluoromethyl-2-pyridyl)methylthio)ethyl]-N"-p-toluenesulphonylguanidine.

EXAMPLE 11N-[2-((3-Chloro-2-pyridyl)methylthio)ethyl]-N'-sulphamylguanidine

a. A solution of 3-chloro-2-((2-aminoethyl)thiomethyl) pyridine (22.4 g)and S-methylisothiourea sulphate (15.1 g) in water (100 ml) was heatedunder reflux for 3 hours. Concentration, acidification with sulphuricacid and dilution with ethanol afforded2-[3-chloro-2-pyridyl)methylthio)ethyl]guanidine sulphate.

b. The guanidine sulphate (10.0 g) was added to a solution of sodium(1.53 g) in ethanol (100 ml). Filtration and concentration gave theguanidine base which was dissolved in dimethylsulphoxide (20 ml) andadded gradually to a solution of N-piperidylsulphamide (5.3 g) indimethylsulphoxide (10 ml). The mixture was heated on the steam bath for2 hours and concentrated under reduced pressure. The residue waschromatographed on a column of silica gel yielding a product (2.38 g)which was recrystallised to giveN-[2-((3-chloro-2-pyridyl)methylthio)ethyl]-N'-sulphamylguanidine.

EXAMPLE 12N-Methyl-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-N"-sulphamylguanidine

a. A solution ofN-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]guanidine(2.2 g) in hydrochloric acid (25 ml) was heated on the steam bath for 2hours. Concentration followed by recrystallisation of the productafforded N-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidinedihydrochloride (1.6 g).

b. The guanidine dihydrochloride (3.2 g) was added to a solution ofsodium (0.46 g) in ethanol (50 ml) and following warming with stirringfor 0.5 hours, the mixture was cooled and filtered,N-piperidylsulphamide (1.64 g) was added to the filtrate which washeated under reflux or 24 hours. Following concentration the residue waschromatographed firstly on silica gel and then on alumina to yieldN-methyl-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-N"-sulphamylguanidine.

EXAMPLE 13N-(4-Aminobenzenesulphonyl)-N'-methyl-N"-[2-(3-bromo-2-pyridyl)methylthio)ethyl]guanidine

a. The reaction of 4-aminobenzenesulphonamide (17.2 g) with sodiumhydroxide, carbon disulphide and methyl iodide by the method describedin Example 8, afforded N-(4-aminobenzenesulphonyl)iminodithiocarbonicacid dimethyl ester (9.4 g), m.p. 202°-204° (from ethanol).

b. The reaction of N-(4-aminobenzenesulphonyl)iminodithiocarbonic aciddimethyl ester (8.9 g) with 3-bromo-2-((2-aminoethyl)thiomethyl)pyridine(8.2 g) and methylamine by the method described in Example 7, followedby chromatographic purification on a column of alumina afforded(N-(4-aminobenzenesulphonyl)-N'-methyl-N"-[2-((3-bromo-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 14N-Acetyl-N'-[2-((3-methyl-2-pyridyl)methylthio)ethyl]guanidine

N-Acetyl-S-methylisothiouronium iodide (5.20 g) was dissolved inacetonitrile (100 ml), excess solid potassium carbonate added and thesuspension stirred at room temperature for 0.5 hours. Followingfiltration, 3-methyl-2-((2-aminoethyl)-thiomethyl)pyridine (3.6 g) wasadded and stirring was continued at room temperature for 48 hours. Thewhite solid formed during the reaction was collected and recrystallisedto give N-acetyl-N'-[2-((3-methyl-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 15N-Carbethoxy-N'-[2-((6-methyl-2-pyridyl)methylthio)ethyl]guanidine

A solution of N-carbethoxy-O-methylisourea (1.46 g) and 6-methyl-2-((2-aminoethyl)thiomethyl)pyridine (1.9 g) in methanol (25 ml) wasstirred at room temperature for 7 days. The white solid formed duringthe reaction was collected and recrystallised to giveN-carbethoxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine.

EXAMPLE 16N-Carbamyl-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]guanidinedihydrochloride

A solution ofN-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]guanidine(1.4 g) in N hydrochloric acid (15 ml) was kept at room temperature for60 hours, and then heated at 40°-45° for 20 hours. Followingconcentration and basification with sodium ethoxide in ethanol, theproduct was chromatographed on silica gel. Acidification with ethanolichydrogen chloride and final recrystallisation affordedN-carbamyl-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidinedihydrochloride.

EXAMPLE 17N-Methyl-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-N"-thiocarbamylguanidine

Gaseous hydrogen sulphide was passed through a solution ofN-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]pyridine(5.4 g) in pyridine (45 ml) containing triethylamine (9 ml) at roomtemperature for 24 hours and at 50° for a similar period. Concentration,followed by chromatographic purification on a column of silica gel andacidification with ethanolic hydrogen chloride affordedN-methyl-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-N"-thiocarbamylguanidine.

EXAMPLE 18N-Benzylideneamino-N'-methyl-N"-[2-((3-chloro-2-pyridyl)methylthio)-ethyl]guanidine

A solution of benzaldehyde-4-methylthiosemicarbazone (3.9 g) andmethyliodide (11.2 g) in absolute ethanol (40 ml) was heated underreflux for 16 hours. Concentration and recrystallisation from ethanolafforded the S-methylisothiouronium iodide (5.3 g) m.p. 194°-196°, whichwas basified with aqueous sodium carbonate and extracted with ethylacetate to afford the base (2.5 g). This was dissolved in ethanolcontaining 3-chloro-2-((2-aminoethyl)-thiomethyl)pyridine (2.0 g) andthe solution heated under reflux for 3 days. Concentration followed bypurification on a solumn of silica gel affordedN-benzylidenamino-N"-[2-((3-chloro-2-pyridyl)methylthio)ethyl]guanidine.

EXAMPLE 19

Sequential reaction of N-benzenesulphonyliminodithiocarbonic aciddimethyl ester according to a process similar to that described inExample 1 with any of the following substances:

a. 3-[4-aminobutyl]pyridine.

b. 5-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine

c. 2-((2-aminoethoxy)methyl)pyridine

d. N-(3-bromo-2-picolyl)ethylenediamine

and then with excess methylamine results respectively in the productionof the following compounds:

a. N-benzenesulphonyl-N'-methyl-N"-[4-(3-pyridyl)butyl]-guanidine

b.N-benzenesulphonyl-N'-methyl-N"-[2-((5-hydroxy-2-pyridyl)methylthio)ethyl]guanidine

c.N-benzenesulphonyl-N'-methyl-N"-[2-((2-pyridyl)methoxy)-ethyl]guanidine

d.N-benzenesulphonyl-N'-methyl-N"-[2-((3-bromo-2-pyridyl)-methylamino)ethyl]guanidine.

EXAMPLE 20

Sequential reaction of N-benzenesulphonyliminodithiocarbonic aciddimethyl ester according to a process similar to that described inExample 1 with either of the following compounds:

a. 2-[(2-aminoethyl)thioethyl]pyridine

b. 2-[(3-aminopropyl)thio]pyridine

and then with excess methylamine results respectively in the productionof the following compounds:

a.N-benzenesulphonyl-N'-methyl-N"-[2-((2-pyridyl)ethylthio)-ethyl]guanidine

b. benzenesulphonyl-N'-methyl-N"-[3-((2-pyridyl)thio)-propyl]guanidine.

EXAMPLE 21

Reaction of the amines set out in Example 19 withN-benzenesulphonyliminodithiocarbonic acid dimethyl ester as describedtherein and then with ethylamine or with butylamine resultedrespectively in the corresponding compounds of Formula I wherein R₁ isethyl or butyl.

EXAMPLE 22INGREDIENTSAMOUNTS______________________________________N-benzenesulphonyl-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)-methylthio)-ethyl]guanidine150 mg.sucrose 75 mg.starch 25 mg.talc 5 mg.stearic acid 2mg.______________________________________

The ingredients are screened, mixed and filled into a hard gelatincapsule.

We claim:
 1. A compound of the formula: ##EQU6## wherein R₁ is hydrogenor lower alkyl; R₂ is a grouping of the formula:

    Het -- (CH.sub.2).sub.m Z(CH.sub.2).sub.n --

wherein Het is a pyridyl ring which is optionally substituted by loweralkyl, trifluoromethyl, hydroxy, halogen or amino; Z is sulphur, oxygen,NH or a methylene group; m is 0, 1 or 2 and n is 2 or 3, the sum of mand n being from 2 to 4; X is SO₂ R₄ or N=CHR₅ R₄ is phenyl optionallysubstituted by halogen, lower alkyl or amino; and R₅ is phenyl or apharmaceutically acceptable acid addition salt of said compound.
 2. Acompound according to claim 1 wherein X is SO₂ R₄ and R₄ has the samesignificance as in claim
 1. 3. A compound according to claim 1 whereinR₁ is methyl.
 4. A compound according to claim 1 wherein Z is sulphur, mis 1 and n is
 2. 5. A compound according to claim 3 wherein Het is apyridyl ring which ring is optionally substituted by methyl, hydroxyl,halogen or amino.
 6. A compound according to claim 1 wherein X isphenylsulphonyl.
 7. A compound according to claim 1, said compound beingN-benzenesulphonyl-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]guanidine.8. A process for the production of a compound according to claim 1wherein an amine of the formula

    R.sub.2 NH.sub.2

wherein R₂ has the same significance as in the formula set out in claim1 is reacted with a compound of the formula ##EQU7## wherein R₁ and Xhave the same significance as in the formula set out in claim 1; Y issulphur or oxygen; and A is lower alkyl.
 9. A process for the productionof a compound according to claim 1 wherein an amine of the formula

    R.sub.2 NH.sub.2

wherein R₂ has the same significance as in the formula set out in claim1 is first reacted with a compound of the formula

    (A--Y).sub.2 C=N -- X

wherein X has the same significance as in the formula set out in claim1; Y is sulphur or oxygen; and A is lower alkyl to give an intermediatecompound of the formula: ##EQU8##
 10. A pharmaceutical composition toinhibit H-2 histamine receptors, said H-2 histamine receptors beingthose histamine receptors which are not inhibited by mepyramine but areinhibited by burimamide, comprising in an effective amount to inhibitsaid H-2 histamine receptors a compound of claim 1 and a non-toxicpharmaceutically acceptable diluent or carrier.
 11. A method ofinhibiting H-2 histamine receptors, said H-2 histamine receptors beingthose histamine receptors which are not inhibited by mepyramine but areinhibited by burimamide, which comprises administering to an animal inneed of inhibition of said H-2 histamine receptors in an effectiveamount to inhibit said H-2 histamine receptors a compound of claim 1.12. A method of inhibiting gastric acid secretion which comprisesadministering internally to an animal in need of inhibition of gastricacid secretion in an effective amount to inhibit gastric acid secretiona compound of claim 1.